Using 19F NMR and two-level factorial design to explore thiol-fluoride substitution in hexafluorobenzene and its application in peptide stapling and cyclisation

Paolo Dognini, Patrick M. Killoran, George S. Hanson, Lewis Halsall, Talhat Chaudhry, Zasharatul Islam, Francesca Giuntini, Christopher R. Coxon

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Abstract

Hexafluorobenzene undergoes 1,4-selective thiol-fluoride disubstitution and is an attractive disulfide crosslinking reagent for peptide cyclisation and stapling. Little attention has been directed toward understanding the scope of this reaction. Traditional reaction optimisation relies on a one-variable-at-a-time approach, which can exclude important combined effects of reaction variables. This study initially explored base and solvent effects to inform a subsequent two-level factorial design approach to understand how to control the reactivity and product selectivity in a model reaction of hexafluorobenzene. We describe new conditions that selectively afford higher order substitution products for example, 1,2,4,5-tetrasubstitution, making hexafluorobenzene a possible suitable scaffold for future branched or multicyclic peptide systems. Moreover, our new conditions provide an improved rapid (<1 minute) and selective peptide disulfide stapling and cyclisation approach under peptide‐compatible conditions.
Original languageEnglish
Pages (from-to)e24182
JournalPeptide Science
Early online date9 Jul 2020
DOIs
Publication statusE-pub ahead of print - 9 Jul 2020

Keywords

  • 19F NMR
  • design of experiments
  • factorial design
  • hexafluorobenzene
  • peptide stapling

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